4-氰基-5-芳基-1H-1,2,3-三氮唑的合成及酪氨酸激酶抑制活性研究  

Synthesis of 5-aryl-4-cyano-1H-1, 2, 3-triazoles and biological evaluation of their inhibitory action on tyrosine kinase

作　　者：李文杰[1] 刘素芳[2] 陈缵光[1] 成志毅[1] 

机构地区：[1]中山大学药学院,广州510006 [2]中山大学公共卫生学院,广州510080

出　　处：《药学学报》2009年第12期1371-1375,共5页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(20875105)

摘　　要：叠氮化钠悬浮在DMF溶剂中与芳基丙炔腈在90～120°C下反应6～10h,得到系列4-氰基-5-芳基-1H-1,2,3-三氮唑化合物,共13个。化合物结构经质谱、1HNMR、红外光谱等确证,并用单晶X射线衍射测定了化合物3f和3m的晶体结构,两个结构都表明三氮唑的活泼H在1-N原子上。活性试验表明该系列三氮唑对HER2过表达的乳腺癌细胞的增值有抑制活性,并发现这些化合物对其细胞中HER2磷酸化的抑制活性与其对细胞增值的抑制活性明显相关。其中3k和3l对细胞中酪氨酸激酶磷酸化的半抑制率(IC50)的最低浓度分别为9.7μmol·L-1和6.6μmol·L-1。三氮唑芳基上取代基的吸电子效应对其抑制乳腺癌细胞增值的活性有利。5-Aryl-4-cyano-1H-1, 2, 3-triazoles bearing a variety of substituting groups on 5-phenyl were synthesized. Their structures were established by MS, IR and ^1H NMR spectra. The crystal structures of compounds 3f and 3m were determined by X-ray diffraction analysis. The active H of the tfiazole was on 1-N from the crystal structures. The compounds, designed as HER2 tyrosine kinase inhibitors, were screened for bioactivity of growth-inhibition of breast cancer MDA-MB-453 cells. The lowest IC50 value of inhibiting HER2 tyrosine kinase phosphorylation in breast cancer cells is 6.6 gmol.L^-1. The inhibiting-growth of breast cancer cells was enhanced from electron-drawing groups joining 5-phenyl on the triazole.

关 键 词：4-氰基-5-芳基-1H1  2  3-三氮唑 晶体结构 生物活性 

分 类 号：R916.1[医药卫生—药学]